The advantages of administering orally active drugs in a sustained release form are numerous (see R. J. DeNeale and P. C. Guley, U.S. Pat. No. 4,248,857, Feb. 3, 1981; Remington's Pharmaceutical Science, 1980, Mack Publishing Co., Easton, PA 1590-1593).
It is also known, of course, that taking medication once a day instead of numerous times daily, especially for combinations such as diuretics with different pharmacodynamic actions eliminates a major source of inconvenience and insecurity for the patient as well as proving for a more even distribution of drug concentration in the blood. According to the pH-partition theory the absorbability of furosemide and triamterene, respectively, is favored when they are present in uncharged form at the absorption site and possess an intrinsic partition coefficient favoring a system like oil in an oil-water system. Since charged materials are oil-insoluble, those properties of drugs favoring their existence in fluids at absorption sites in the uncharged form favor their absorption. So furosemide as a weakly acidic drug will exist in the stomach in the undissociated form, and, therefore, its absorption will be favored from this pH-environment resulting in fairly quick action with considerable loss of potassium. Triamterene which is a weakly basic drug will exist at the same site as a protonated cation, hence charged and poorly absorbed which is consistent with in vivo experiments revealing a pharmocokinetic half life time of t.sub.1/2 =3.0 h versus t.sub.1/2 =1.5 h for furosemide in comparison.
Furosemide, peritanide, and bumetanide are advantageous in the treatment of edema and high blood pressure. They have a half life time of about 1 h versus 4 h in the case of the benzothiadiazides derivatives, for instance. The consequence of the very strong effect may be circulation problems which may even cause a collapse. Further undesirable pharmacological effects are inter alia an increase in uric acid, diabetogenous effects, influence on the metabolism, strong potassium losses and the massive stimulation of the plasma renin-angiotensin system.
From DE-AS No. 26 15 694 the combination of triamterene with cyclothiazide is known. When the individual dose is reduced, stronger total effects and fewer undesirable pharmaceutical side effects were observed also. However, the precondition for an ideal combination is the requisite that both active ingredients are almost identical in their pharmacokinetic half life time and supplement each other in their pharmacodynamics.
From Therapiewoche 30, 1980, pages 6831 to 6847 it is known that by the simultaneous intravenous administration of furosemide and hydroxy-triamterene-sulfuric acid ester, which attains a plasma concentration about ten times greater than triamterene, the potassium loss caused by furosemide can be impeded.
Celdran et al., (Arzneimittel-Forschung 1976, 26(11), 2073-2076) describe a preparation having diuretic activity consisting of 40 mg of furosemide Xanthinol and 25 mg triamterene which was given to patients separately.
Thompson et al., (Clin. Pharmacol. Ther., 1977, 21(4), 392-394) describe the effect upon administration of 40 mg/day of furosemide and 50 mg/day or 100 mg/day of triamterene. Both doses of triamterene are stated to agument the natriuretic effect. The dosage was determined empirically.
Stote et al., (J. Int. Med. Res., 1974, 2(6), 379-383), describe the oral dose of triamterene, 50 or 100 mg, required to block the kaliuretic effect of 40 mg furosemide in normal volunteers.
Azzi et al., (Clin. Ter., 1971, 56(6), 501-522) show the use of 80 mg of furosemide with 50 mg triamterene when administered to edema-bearing patients.
Lammintausta et al., studied the excretion and electrolyte excretion following administration of 80 mg furosemide and 100 mg of triamterene to healthy volunteers. (Lammintausta et al., Int. J. Clin. Pharmacol. Ther. Toxiol., 1980, 18(9), 395-398).
The patent ot Dahlhausen et al. No. 4,324,779 simply shows a slightly retarded formulation of furosemide including measurments and releases rates. As will be discussed later on with more particularity the method of Dahlhausen et al. will give false results when another diuretic is present in a combination of drugs with respect to dissolution rates and not simply release rates and physical state in solution.
The patent to Johnsen (U.S. Pat. No. 4,335,119, June 15, 1982) shows a pharmaceutical preparation of furosemide with the sulfate ester of 2,4,7-triamino-6-p-hydroxy-phenylpteridine and its physiologically permissible salts in a weight ratio of 1:10 to 5:1 (furosemide:pteridine component) with a preference of 1:4 to 2:1. Other researchers report chemical and pharmacodynamic results of various dosage forms of furosemide and triamterene administered separately manifesting the potassium loss through furosemide and its inhibition through triamterene (Azzi et al., Clin. Ter., 1971, 56(6), 501-522; Celdran et al., Arzneim.-Forschung 1976, 26(11), 2073-2076; Stote et al., J. Int. Med. Res., 1974, 2(6), 379-383; Lammintausta et al., Int. J. Clin. Pharmacol. Ther. Toxicol., 1980, 18(9), 395-398).
None of the foregoing references, showing various combinations in unrelated stoichiometry of furosemide and triamterene, teach the desirability of providing (i) a constant molar ration of furosemide to triamterene by an appropriate pharmaceutical formulation, yielding mixed micelles in aqueous solutions at pH 1.5 to pH 7.5, demonstrating that these mixed micelles are the physicochemical active pharmacons; (ii) nor do the references teach how to achieve these mixed micelles with high stability and low polydispersity in due time, e.g. indicating the very reduced concentrations of furosemide and triamterene-monomers in aqueous solutions; and (iii) the synergistic effect of reducing the dissolution rate of furosemide by triamterene through forming mixed micelles comprising binding furosemide onto triamterene micelles, quite unexpectedly at a constant ratio of furosemide to triamterene of 1.0:2.0.
It is, therefore, an object of the present invention to provide a novel pharmaceutical composition comprising furosemide, having a controlled release rate, and triamterene in a ratio of 1.0:2.0 (mol/mol) of low polydispersity and high stability.
It is a further object of the present invention to provide a new pharmaceutical combination of acidic and basic diuretically active ingredients with the formation of mixed micelles, induced through a controlled release form of furosemide which forms instantly mixed micelles in aqueous solutions with triamterene in a constant ratio of the former to the latter of 1.0:2.0.
These and other objects of the present invention are readily achieved by providing a potassium-neutral salureticum with anti-hypertensive effect by using a novel preparation of a combination of a controlled release form of furosemide and triamterene, having the following pharmacological properties at a constant ratio of 30 mg furosemide in controlled release form and 50 mg triamterene:
1. Rapid initial onset of the effect. PA0 2. No abrupt and short effect, i.e. no rebound. PA0 3. Maximally protracted effect lasting more than 10. h. PA0 4. Good and simultaneously protective flooding out without circulation stress and without danger of thrombosis. PA0 5. Effective even where the kidney function is restricted. PA0 6. Potassium neutral, saving in magnesium and calcium ions. PA0 7. As far as possible without influence on carbohydrate and fat metabolism as well as the separation of uric acid is concerned. PA0 8. Less side effects, e.g. stomach disturbances due to triamterene.